How multiple sclerosis (MS) begins remains unknown. The earliest lesions studied, fixed hours after onset of symptoms, exhibit oligodendrocyte apoptosis, blood-brain barrier (BBB) permeability, and early microglial activation.1-6 In these nascent lesions, demyelination is not yet apparent, there are no lipid-laden macrophages and there is the conspicuous absence of infiltrating lymphocytes.1-8 The absence of an inflammatory infiltrate in nascent lesions argues against MS beginning as an autoimmune phenomenon and instead favors a toxin or viral etiology. Hence it seems reasonable that the environmental trigger for initial lesion formation in MS might be a soluble toxin based on the histopathologic features of the nascent lesion.
Clostridium perfringens is a gram positive, spore forming anaerobe that is sub-categorized into five toxinotypes based on combinatorial carriage of α, β, ε and ι toxins9-11 (Table 1).
TABLE 1Clostridium perfringens toxinotypesand known associated human diseases.ToxinotypeToxin CarriageHuman DiseasesAαFood-born illness, diarrhea, toxic enteritis,gangreneBα, β, εNone knownCα, βNecrotic enteritis (Pig-bel. Darmbrand)Dα, εRare toxic enteritisEα, ιNone known
C. perfringens types B and D carry the epsilon toxin (ETX) gene, which encodes a 33 kD protoxin of the epsilson toxin. With log phase growth, protoxin is secreted and cleaved by trypsin and chymotrypsin in the gastrointestinal (GI) tract or by the C. perfringens encoded λ-protease, yielding an active epsilon toxin (ETX) which is ˜1,000× more potent than the protoxin.11 
The natural hosts for C. perfringens toxinotypes B and D are ruminant animals in whom ETX-mediated neurologic symptoms occur when carbohydrate rich feed or over grazing favors exponential growth of the bacilli.11 ETX is absorbed via the intestine, enters the blood stream and permeabilizes the BBB, resulting in MS like symptoms (e.g. visual dysfunction, incoordination and spastic paralysis). Murrell and colleagues, because of these effects on the CNS,12,13 first suggested ETX as a potential MS trigger in animals, such as sheep, although humans are not natural hosts for types B or D.11,14 
ETX binds to a previously unknown receptor present both in the brain vasculature and myelinated brain regions, e.g., corpus callosum.15-17 Once bound to its receptor, ETX integrates into the plasma membrane as a heptameric pore, leading to osmolysis.11,14 When ETX is administered to rodents, BBB disruption occurs and white matter vasculature is especially vulnerable.16,17 Interestingly, intraperitoneal administration of protoxin in rats results in the formation of focal ovoid lesions within the corpus callosum, in which the long axis of the ovoid is oriented perpendicular to the surface of the lateral ventricle.18 Dawson first described this specific lesion morphology and the radiographic equivalent of demyelination surrounding a central vennule is pathognomonic for clinically definite multiple sclerosis.19 